34 SCIENTIFIC AMERICAN AUGUST 2005
CREDIT
More complicated than they look,
teeth are actually tiny organs.
If tissue engineers
can manufacture living replacement teeth,
they would blaze a trail for engineering larger organs
while leading dentistry into the age of regenerative medicine
Te s t -Tu b e Te e t h
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CREDIT
By Paul T. Sharpe and Conan S. Young
COPYRIGHT 2005 SCIENTIFIC AMERICAN, INC.
36 SCIENTIFIC AMERICAN AUGUST 2005
or require major repairs. And then the options are grim: do
without lost teeth or replace them with inert prosthetic ver-
sions. In the Western world, an estimated 85 percent of adults
have had some form of dental treatment. Seven percent have
lost one or more teeth by age 17. After age 50, an average of
12 teeth stand to have been lost.
In theory, a natural tooth made from the patient’s own
tissue and grown in its intended location would make the best
possible replacement, although such bioengineered teeth have
for many years been little more than a dream. Recently, how-
ever, progress in understanding how teeth fi rst develop has
combined with advances in stem cell biology and tissue engi-
neering technology to bring us close to the realization of bio-
logical replacement teeth.
Apart from the potential bene t to people who need new
teeth, this research also offers two signi cant advantages for
testing the concept of organ replacement: teeth are easily ac-
cessible, and whereas our quality of life is greatly improved if
we have them, we do not need our teeth to live. These may
seem trivial points, but as the fi rst wave of replacement organs
start to make their way toward the clinic, teeth will serve as
a crucial test of the feasibility of different tissue engineering
techniques. With organs essential to life, doctors will have no
leeway to make mistakes, but mistakes with teeth would not
be life-threatening and could be corrected.
This is not to say that engineering teeth will be simple. Mil-
lions of years of evolution went into establishing the complex
processes that produce organs, teeth included, during embry-
onic development. The challenge for tissue engineers is to rep-
licate those processes, which are tightly controlled by the
growing embryo’s genes. A good way to start learning how to
build teeth, therefore, is to observe how nature does it.
Delicate Dialogue
just six weeks after conception, a human embryo is less
than an inch long and barely beginning to take recognizable
shape. Yet a constant cross talk among its cells is already ini-
tiating and guiding the formation of its teeth. The intricacy
of such signal exchanges is among the reasons that teeth and
other organs cannot as yet be grown entirely in dishes in lab-
oratories. Indeed, scientists may never be able to completely
reproduce these conditions arti cially. The more we under-
stand these early developmental processes, however, the
greater will be our chances of providing engineered tooth tis-
sues with the most important cues for organ building and
letting nature do the rest.
Most organs, for example, arise through interactions be-
tween two distinct embryonic cell types, epithelial and mes-
enchymal, and teeth are no exception. In the embryo, oral
epithelial cells (which are destined to line oral cavities) send
out the fi rst inductive signals to mesenchymal cells (which will
produce jawbone and soft tissues), instructing them to begin
odontogenesis, or tooth formation. Once the mesenchymal
cells have received their initial instructions, they start sending
signals back to the epithelial cells. This reciprocal exchange
continues throughout embryonic tooth development.
At fi rst, the future tooth is no more than a thickening in
the embryonic oral epithelium. As it grows, the epithelium
begins to penetrate the underlying mesenchymal tissue, which
in turn condenses around the protrusion, forming a tooth bud
by the embryo’s seventh week [see box on opposite page]. As
the epithelium penetrates farther, it wraps itself around the
condensing mesenchyme, eventually forming a bell-shaped
structure, open at its bottom, around 14 weeks. Ultimately,
the epithelium will become the visible outer enamel of the
tooth that erupts from the babys gum line some six to twelve
months after birth, and the mesenchymal cells will have
formed the nonvisible parts of the tooth, such as dentin, den-
tal pulp, cementum, and a periodontal ligament that attaches
the tooth to the jawbone.
Even before this tooth begins forming, its shape will be
predetermined by its position. Some of the same epithelial
signals that trigger initiation of odontogenesis also regulate
Tissue engineers working toward creating living
replacement teeth take cues from nature as they coax
disparate cell types to form a functional organ.
Alternative methods include building teeth from existing
dental cells or growing them from progenitor tissues.
Both approaches have already produced structurally
correct teeth.
Remaining challenges include growing roots and
identifying ideal raw materials for bioengineered human
teeth, but progress has been rapid and test-tube teeth
may become the fi rst engineered organs.
Overview/Cutting-Edge Teeth
We take them for granted until they are gone
CARY WOLINSKY (photography); JEN CHRISTIANSEN (photoillustration) (preceding pages)
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HOW NATURE ENGINEERS A TOOTH
TOOTH FORMATION
Just six to seven weeks into human embryonic development, when the whole head is
still taking shape, teeth are also beginning to form. At the location of a future tooth, oral
epithelial tissue thickens slightly and gene activity within its cells causes signals to be sent
to underlying mesenchymal tissue. As the epithelium penetrates farther, mesenchymal
cells respond by emitting their own signals and condensing around the protrusion to form
a tooth bud. By week nine, the epithelium has become a cap atop condensed mesenchyme.
A structure at its center called the enamel knot is now a primary source of signals directing
the activity of both epithelial and mesenchymal cells. At 14 weeks, the tooth germ has a bell
shape comprising differentiating cells called ameloblasts, which will later become enamel, and
odontoblasts, which will form dentin. Roots are the last structures to develop, completing their
formation as the tooth erupts some six to 12 months after birth.
It may look simple from the outside, but on the inside a tooth is
a tiny marvel of design and construction that takes about 14
months to complete in a developing human. Two different types
of primordial embryonic tissue combine to produce a tooth,
and an ongoing molecular dialogue between them directs the
process. Tissue engineers are studying these signals and
steps to understand the cues they need to replicate as they
create living bioengineered replacement teeth.
END RESULT
A living tooth is de ned as an organ because
it comprises multiple tissue types, each
with an essential function. Enamel, the body’s
hardest mineralized surface, seals and protects
the interior. Dentin, a bony substance, makes
up the bulk of a tooth and serves as a cushion
to resist chewing forces. Pulp, in the center,
contains nourishing blood vessels and nerves
that provide sensory perception. Cementum
forms the hard outer surface of a tooth where it
is not covered by enamel. Periodontal ligament
is a connective tissue that attaches to both the
cementum and the jawbone, anchoring the tooth
in place yet providing some fl exibility.
Embryo at 6 weeks
Thickening: 42–48 days
Tooth bud: 7 weeks
Enamel knot
Bell stage: 14 weeks
Erupted tooth: 6–12 months after birth
Cap stage: 9 weeks
Enamel
Cementum
Gum
Blood vessels
Nerve
Periodontal
ligament
Jawbone
Root
Enamel
Odontoblasts
Oral epithelium
Dentin
Condensing
mesenchyme
Mesenchyme
Signaling
Ameloblasts
Pulp
ANDREW SWIFT
COPYRIGHT 2005 SCIENTIFIC AMERICAN, INC.
an important category of genes in the jaw mesenchyme.
Known as homeobox genes, they participate in determining
the shape and location of organs and appendages during em-
bryonic development throughout the body. In a developing
human jaw, different homeobox genes are activated in differ-
ent areas, guiding each tooth bud down a pathway to become
a molar, premolar, canine or incisor.
A homeobox gene called Barx1, for example, is switched
on, or expressed, by mesenchymal cells in the positions where
molar teeth will grow. In animal experiments, causing Barx1
to be misexpressed in mesenchyme that would normally form
incisors makes those teeth develop with a molar shape in-
stead. Because the ability to predict and control tooth shape
will be essent ial for the creation of engineered teeth, scientists
can use the activity of genes such as Barx1 as defi nitive predic-
tive markers of future shape when teeth created in the lab are
rst growing in culture.
In turn, we must provide the right signals to the developing
teeth at the right time. As early as the 1960s, researchers such
as Shirley Glasstone of Strangeways Research Laboratory in
Cambridge, England, began exploring the possibility of grow-
ing teeth by experimenting with mouse tissues. In seminal
studies performed over the next three decades, tiny pieces of
embryonic mouse dental epithelium and dental mesenchyme
were brought together and then either grown in a tissue culture
dish or surgically implanted in the body of a host where the
recombined tissues would receive a blood supply. These ex-
periments demonstrated that such embryonic tooth primordia
could continue to develop as if they were still in the embryo,
producing dentin and enamel. Their development arrests ear-
ly, however, and they do not ultimately yield fully formed
teeth. Something is missing from their environment.
The growth factors and other signals required to complete
tooth formation in an embryo most likely come from sur-
rounding jaw tissue. Thus, transplanting tooth primordia into
the jaw to fi nish developing would seem to be a simple solu-
tion. When replacement teeth are engineered, for instance,
they will ideally be grown in their permanent location so that
they can create nerve and blood vessel connections and phys-
ically attach themselves to the jawbone. The adult jaw is a
vastly different environment from the embryonic version,
however, and scientists have been unsure whether it would
provide the correct signals to a developing tooth.
Moreover, tooth primordia must be constructed from the
right combination of cells to reproduce natural tooth mate-
rial and structure. Being able to use cells from a patient’s own
body would be preferable to using embryonic cells because
the patient’s own tissue would not be perceived as foreign and
so would not provoke an immune response.
Three key milestones must therefore be reached to estab-
lish whether engineering replacement biological teeth is pos-
sible. Sources of cells that can form teeth and are easily ob-
tained from patients themselves must be identifi ed. The teeth
produced from these cells must be able to develop in the envi-
ronment of the adult jaw, producing roots that are attached to
Cells Reunite to Form Teeth
Tooth cells taken from adolescent pigs and seeded onto a
biodegradable scaffold are visible in blue along its edges
after one week of incubation (top left). Following 25
weeks of growth (top right), the scaffold has dissolved and new
dental pulp, enamel, and dentin have taken its place. In a series
of such experiments, tiny toothlike structures grew amid the
new tissues. Correct tooth-tissue organization (bottom left),
including a pre-root structure known as Hertwig’s epithelial
root sheath (Hers), was observed in 15 to 20 percent of the
miniature teeth. In other instances, the tooth structure was
incorrect or incomplete (bottom right). These bioengineered
teeth nonetheless seem to confi rm that disaggregated dental
cells can reorganize themselves into larger dental tissues.
Pulp
Scaffold
Hers
Enamel
Dentin
Predentin
Odontoblasts
Dentin
Dentin
Tooth cells
Pulp
Pulp
Enamel
REPRINTED FROM DEVELOPMENTAL ANALYSIS AND COMPUTER MODELLING OF BIOENGINEERED TEETH, BY C. S. YOUNG ET AL. IN ARCHIVES OF ORAL BIOLOGY,
VOL. 50, PAGES 259–265; 2005. WITH PERMISSION FROM ELSEVIER (top left and right; bottom right); CONAN S. YOUNG (bottom left)
38 SCIENTIFIC AMERICAN AUGUST 2005
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the bone by a functional periodontal ligament. And the shape
and size of these biological teeth must be predictable and con-
trollable so that they can be made to match the patient’s own
teeth. These are ambitious goals, but considerable progress
toward each is being made by different research groups using
somewhat disparate approaches.
Building Bioteeth
in the late 1980s organ transplant surgeon Joseph P.
Vacanti of Harvard Medical School and polymer chemist Rob-
ert S. Langer of the Massachusetts Institute of Technology
conceived the idea of placing the cells of an organ or tissue on
a prefabricated biodegradable scaffold with the goal of gener-
ating tissues and organs for transplantation [see “Arti cial
Organs, by Robert S. Langer and Joseph P. Vacanti; Scien-
tifi c American, September 1995]. In simplifi ed terms, their
approach was based on the fact that living tissues are made of
cells constantly signaling to one another and often moving
around within a three-dimensional community of sorts. Each
cell seems to know its place and role in the larger collective that
forms and maintains a functional tissue. Therefore, if the right
mix of dissociated cells is reaggregated within a scaffold that
replicates their natural 3-D environment, the cells should in-
stinctively reform the tissue or organ to which they belong.
Vacanti and Langers early successes regenerating pieces of
liver tissue from liver cells using this scaffold-based strategy
have since led to widespread experimentation with the tech-
nique to produce other complex tissues, such as heart muscle,
intestine, mineralized bone and now teeth. Pamela C. Yelick
and John D. Bartlett of the Forsyth Institute in Boston began
working with Vacanti in 2000 to investigate the feasibility of
engineering teeth this way by focusing on pigs, which, like
humans, produce two sets of teeth over their lifetime.
One of us (Young) also took part in these experiments for
which raw material was derived from the unerupted third mo-
lars (“wisdom teeth”) of six-month-old pigs. To obtain a het-
erogeneous random mixture of dental enamel epithelial and
pulp mesenchymal cells, the pig teeth were broken into tiny
pieces and then further dissolved using enzymes. Tooth-
shaped scaffolds were made from biodegradable polyester
plastics and coated with a substance that makes the plastic
sticky so cells can adhere to it. The cell mixtures were seeded
into the scaffolds, and the constructs were surgically implant-
ed into rat hosts, wrapped in omentum, a fatty white material
rich in blood vessels that surrounds the intestines. This step is
important because the developing tooth tissues require an
ample blood supply to provide them with nutrients and oxygen
while they grow.
Initially the scaffolds provided support for the cells, but
later they dissolved as intended and were replaced by new tis-
sue. When the implants were examined after 20 to 30 weeks,
tiny toothlike structures were visible within the confi nes of the
original scaffold. Their shape and the organization of their
tissues resembled the crowns of natural teeth [see box on op-
posite page]. They also included most of the tissues that make
up a normal tooth, demonstrating for the fi rst time that enam-
el, dentin, pulp, and features that appeared to be developing
tooth roots could be regenerated on scaffolds.
It seemed that mixtures of dental cells could reorganize
themselves on scaffolds into arrangements that favor forma-
tion of mineralized enamel, dentin and soft tooth tissue. An-
other possible explanation for these exciting results, of course,
was that the random arrangement of cells seeded onto the scaf-
fold favored tooth tissue development only by chance. The
Forsyth group therefore tested these possibilities in a new
study using dental epithelial and mesenchymal cells isolated
from the fi rst, second and third molars of rats. This time, how-
ever, the cells were grown and their numbers expanded in tis-
sue culture for six days before their being seeded onto scaffolds
and implanted in rat hosts. After 12 weeks’ growth, the result-
ing tissues were extracted and examined. Once again, small
tooth structures consisting of enamel, dentin and pulp tissue
were observed to have formed within the original scaffold.
These new results were encouraging because they lent some
weight to the previous evidence that cells can reorganize them-
Each cell seems to know
its place in
the larger collective.
PAUL T. SHARPE and CONAN S. YOUNG met two years ago at a
tooth and bone conference where they discovered a shared
fondness for mountain biking and soccer (one calls it “foot-
ball”), despite their differing approaches to bioengineering
teeth. Sharpe established and heads the department of cranio-
facial development at Guys Hospital in London and is also Dick-
inson Professor of Craniofacial Biology at King’s College Lon-
don. In 2002 he founded Odontis Ltd., a biotechnology company
devoted to growing human teeth and bone by emulating their
formative processes in a developing embryo. Young is an in-
structor in oral and developmental biology at the Harvard
School of Dental Medicine and a staff scientist at the Forsyth
Institute in Boston, where he is working toward growing teeth
from cells seeded onto biodegradable scaffolds.
THE AUTHORS
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40 SCIENTIFIC AMERICAN AUGUST 2005
selves into tooth-forming con gurations. Moreover, the cells
did not appear to have been adversely affected by being ex-
panded in culturea process that will be essential in engineer-
ing human replacement teeth because tissue engineers would
probably have to craft a replacement tooth from small samples
of the patient’s own cells. And, fi nally, the experiment demon-
strated that tooth regeneration is possible in a second mam-
mal, making the success of a similar approach in humans more
likely.
Although the Forsyth team was able to generate most of
the desired tissue types with cells from an adult source, those
tissues organized themselves into the proper arrangement for
a natural tooth only 15 to 20 percent of the time. The group is
therefore continuing to work on methods of more precisely
placing different dental cell types within scaffolds to achieve
a more accurate tooth structure.
At the same time, the team is exploring the possibility that
the new tooth tissues observed in these experiments might not
have been produced solely by reorganization of the dissociated
dental cells. Instead the third molar tooth buds that provided
cells to seed the scaffolds might have contained hidden stem
cellspotent progenitors of other cell typesthat were re-
sponsible for forming the new tissue. If true, this would mean
that new dental stem cells capable of producing nearly all the
dental tissue types required for bioengineering teeth might
exist within teeth themselves, at least until early adulthood,
when wisdom teeth erupt. Such versatile adult dental stem cells
would certainly speed efforts to generate teeth on scaffolds,
and they might also facilitate the tooth-engineering approach
used by the Sharpe group at Kings College London.
Teeth from Scratch
rather than attempting to build adult teeth from
their const it uent cells, one of us (Sharpe) is pursuing a strategy
based more closely on reproducing the natural processes of
embryonic tooth development described earlier. In essence, the
method requires an u nderstanding of the basic principles con-
trolling early tooth formation and a source of cells to play the
roles of embryonic oral epithelium and mesenchyme.
To date, the Sharpe group has experimented primarily
with mouse cells, using both stem cells and ordinary cells,
from embryonic as well as adult sources, to test the potential
of various cell types to produce replacement teeth. In most
cases, the group began by aggregating mesenchymal cells in a
centrifuge until they formed a small solid mass. This pellet was
then covered in epithelium and cultured for several days, while
the gene activity in its tissues was monitored for indications of
early tooth development. Next, these tooth primordia were
implanted into the bodies of animal hosts in locations where
they could receive a nourishing blood supply, such as the kid-
ney of a mouse, and left to grow for about 26 days.
In the course of these experiments, clear tooth formation
was observed but only when the epithelium came from an em-
bryonic source and the mesenchymal cell populations con-
tained at least some stem cells. When stem cells from adult
bone marrow took the place of oral mesenchyme, for example,
the transplanted constructs produced structurally correct
teeth. Thus, it seems embryonic mesenchyme can be replaced
with adult stem cells to generate new teeth.
Unfortunately, many years of experiments have established
that embryonic epithelium contains a unique set of signals for
odontogenesis that disappear from the mouth after birth. The
Sharpe group is continuing to seek an effective population of
substitute cells that could be derived from an adult source.
Still, the results achieved with primordia made from the com-
bination of adult stem cells and embryonic oral epithelium
have been extremely encouraging.
Signi cantly, these teeth were also in the normal size range
for mouse teeth, they were surrounded by new bone and con-
nective tissue, and they showed the earliest signs of root forma-
tion. The next step was to see whether such explants could also
form teeth in the mouth. In the embryonic jaw, soft tissues,
teeth and bone are all developing together without external
stresses such as chewing and talking, whereas the adult jaw is
a hard, busy place. No one knew whether it would provide the
necessary signals for teeth to form and integrate themselves
into the environment as they would in an embryo.
To nd out, the Sharpe group extracted tooth buds from
embryonic mice, then transplanted them into the mouths of
adult mice. Small incisions were made in the soft tissue of the
upper jaw of the host mice, in a region known as the diastema
between the molars and incisors where normally there are no
teeth. The embryonic tooth primordia were inserted into
these pockets and sealed in place with surgical glue. After-
ward, the mice were fed a soft diet and the transplants moni-
tored. Just three weeks later teeth could be clearly identi ed
in the diastema. They had formed in the correct orientation,
were of appropriate size for the mice, and were attached to
underlying bone by soft connective tissue [see illustration on
opposite page].
No one knew whether the
adult jaw would provide signals for
teeth to form.
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Remarkably, it appears that the adult mouth can provide a
suitable environment for tooth development. That is just one
of the three milestones toward engineering replacement teeth
that we identifi ed earlier, however. The road to human bioen-
gineered teeth may yet have a few twists.
On the Cusp
compared with efforts to engineer other organs,
teeth have made considerable progress in a short time. The
overall challenge remains developing methods that are simple
yet controlled.
Another of the targets that we established, the ability to
predict and control tooth size and shape, is close. In cultured
primordia, molar and incisor tooth germs can easily be dis-
tinguished by their appearance and their gene activity, al-
though other shapes found in the human mouth, such as pre-
molars and canines, are more dif cult.
The teeth grown from embryonic primordia in the mouths
of adult mice by the Sharpe group displayed shapes appropri-
ate to their original locations in the embryomolar primor-
dia grew into molar-shaped teeth, for example. Because shape
signals are received at the very start of natural tooth develop-
ment, the embryonic tooth germs were already programmed.
Tissue engineers need to better understand these initial shape
signals to induce them in human bioteeth.
To date, the teeth generated by any of the tissue engineer-
ing methods we have described have not developed roots. In
truth, both root development and the stimuli that initiate tooth
eruption are complex and still little understood. Roots are the
last part of teeth to form, completing their development during
the eruption process, and more research is needed to under-
stand what conditions would best favor their creation in re-
placement teeth. Another unknown is how long engineered
human teeth would take to fully form in an adult mouth. Hu-
mans’ second set of “adult” teeth also begins developing in the
embryo, yet those teeth take six to seven years to fi nally
eruptor 20 years in the case of wisdom teeth. Our experience
with tooth generation in animals suggests that an engineered
human tooth would form far more quickly, but we do not
know if it might take longer to fully mature and its enamel to
completely harden.
Of course, most research into bioengineered tooth pro-
duction is also working toward fi nding an effective and easily
accessible source of the patient’s own cells to use as raw mate-
rial. Immune rejection would be avoided, and because tooth
size, shape and color are genetically determined, the engi-
neered teeth would more closely match the patients natural
teeth. The Sharpe group has found that adult mesenchymal
stem cells derived from bone marrow (but also possibly ob-
tainable from fat) can replace embryonic mesenchyme in the
tooth formation process. A substitute for embryonic epithe-
lium has yet to be identi ed, although purported adult stem
cells have been discovered in other tissues with epithelial ori-
gins, such as skin and hair. These or some other adult cell type
may prove effective, perhaps with the aid of gene manipulation
to induce the appropriate initiating signals for odontogenesis.
Of the several potential cell sources, teeth themselves may
be the most convenient. The Forsyth group’s results suggest
that stem cells capable of forming tooth tissues, including
enamel, could be present within teeth. Researchers elsewhere
have also shown that dentin and other tooth tissues experience
some natural regeneration after injury, which, too, suggests
the presence of progenitor cells capable of generating a variety
of tooth tissues. Thus, the possibility exists of someday soon
fashioning new teeth from old.
MORE TO EXPLORE
Tissue Engineering: The Challenges Ahead. Robert S. Langer and
Joseph P. Vacanti in Scientifi c American, Vol. 280, No. 4, pages 8689;
April 1999.
Tissue Engineering of Complex Tooth Structures on Biodegradable
Polymer Scaffolds. Conan S. Young, Shinichi Terada, Joseph P. Vacanti,
Masaki Honda, John D. Bartlett and Pamela C. Yelick in Journal of Dental
Research, Vol. 81, No. 10, pages 695–700; October 2002.
Bioengineered Teeth from Cultured Rat Tooth Bud Cells. Monica T.
Duailibi, Silvio E. Duailibi, Conan S. Young, John D. Bartlett, Joseph P.
Vacanti and Pamela C. Yelick in Journal of Dental Research, Vol. 83,
No. 7, pages 523–528; July 2004.
Stem Cell Based Tissue Engineering of Murine Teeth. A. Ohazama,
S.A.C. Modino, I. Miletich and P. T. Sharpe in Journal of Dental Research,
Vol. 83, No. 7, pages 518522; July 2004.
The Cutting Edge of Mammalian Development: How the Embryo
Makes Teeth. Abigail S. Tucker and Paul T. Sharpe in Nature Reviews
Genetics, Vol. 5, No. 7, pages 499–508; July 2004.
MOUSE TOOTH grown from transplanted molar primordia
in the upper jaw of a host mouse demonstrates that new
teeth can develop in the adult mouth. The tooth at center in this cross
section of the jaw’s diastema region has broken through the gum line
(a second tooth above it and to the right is still forming). Pulp is visible
inside the emerged tooth. Red stain colors dental hard tissues,
highlighting enamel and dentin. Although lacking roots, the tooth is
attached to surrounding jawbone by soft connective tissue.
Connective
tissue
Jawbone
Dentin Pulp
Enamel
Gum
Tooth
MATT BRADMAN
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